The present invention relates to a novel bisaryl compound and a medicament for treatment of cancer which comprises said compound or a known bisaryl compound as an active ingredient.
In the cell proliferation process, DNA replication process is regulated by a family of enzymes relating to nucleic acid synthesis. Among these enzymes, it has been reported that ribonucleotide reductase (occasionally referred to as xe2x80x9cRNRxe2x80x9d hereinafter in this specification) is a particularly important enzyme involved in the biosynthesis of dNTPs, which are precursors of DNA (Ann. Rev. Biochem, 57, pp.349-374).
In cancer cells, endless cell proliferation continues due to over-expression of certain families of enzymes and the like, which leads to death of the host. It has been reported that RNR is over-expressed in cancer cells to maintain high ability of cell proliferation of cancer cells (Cancer Research, 43, pp.3466-3492). Moreover, there has also been reported a possibility that malignant alteration of cancer is caused with accompanying expression of RNR (Proc. Natl. Acad. Sci. USA, 93, pp.14036-14040). Therefore, an agent selectively inhibiting RNR is expected to be able to exert highly selective toxicity to cancer cells, and accordingly, expected to be useful as a medicament for cancer treatment that selectively inhibits the proliferation of cancer cells.
Hydroxyurea has been known as a compound exhibiting antitumor activity by inhibiting RNR, and the compound is used clinically as an anti-leukemia agent. However, the drug only has weak inhibitory activity, and therefore a high blood concentration need to be maintained for a long period of time to successfully inhibit RNR. In addition, the drug causes strong side effects such as bone marrow toxicity, and hence is not a satisfactory therapeutic agent. For these reasons, it has been desired to develop an RNR inhibitor which has potent RNR inhibitory activity as well as reduced side effects including bone marrow toxicity, and has a wide range of effective dosage.
As low molecular RNR inhibitors, there have so far been reported polyhydroxybenzoic acid derivatives (Published Japanese translation of PCT international publication (Kohyo) No. 60-501409/1985), alkoxyphenol compounds (Mol. Pharmacol., 45, pp.792-796), thiosemicarbazone derivatives (Biochem. Pharmacol., 48, pp.335-344), bipyridyl derivatives (Cancer Research, 53, pp.19-26) and the like. However, RNR inhibitory activity and anticancer activity of bisaryl derivatives have not been reported. As for usefulness of bisaryl compounds composed of aryl groups linked by means of plural sulfur atoms as anticancer agents, derivatives comprising aromatic benzenesulfonamide groups as the bisaryl moieties (Japanese Patent Publication (Kokoku) No. 42-10857/1967) have been reported, and the synthesis of an anthramycin dimer has also been reported (Tetrahedron Lett., 129, p.5105). It has also been known that certain bisaryl compounds have antiviral activity (Japanese Patent Unexamined Publication (Kokai) No. 5-501860/1993).
An object of the present invention is to provide a novel bisphenol compound useful as an active ingredient of a medicament.
Another object of the present invention is to provide an medicament for treatment of cancer which comprises a bisphenol compound having inhibitory activity against RNR as an active ingredient.
A still further object of the present invention is to provide a novel bisaryl compound useful as an active ingredient of a medicament.
The inventors of the present invention found that the compounds of the present invention represented by the following formula have inhibitory activity against RNR and anticancer activity, and thus they are useful as an active ingredient of a medicament for treatment of cancer. The present invention was achieved on the basis of these findings.
The present invention provides a medicament for treatment of cancer which comprises a compound represented by the following general formula (I):
Ar1xe2x80x94Sxe2x80x94R1xe2x80x94Sxe2x80x94Ar2 
or a physiologically acceptable salt thereof,
wherein R1 represents a nonmetal bridging group, Ar1 and Ar2 independently represent a group selected from the group consisting of an aryl group which has, on its ring, one or more hydroxyl groups optionally substituted with a monovalent group (the aryl group may have one to three substituents other than a hydroxyl group on its ring), and a heteroaryl group which has, on its ring, one or more hydroxyl groups optionally substituted with a monovalent group (the heteroaryl group may have one to three substituents other than a hydroxyl group on its ring).
Preferred embodiments of the aforementioned invention provided are as follows:
the above medicament for treatment of cancer which comprises a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof, wherein R1 is represented by the general formula (II):
xe2x80x94R2xe2x80x94N(R4)xe2x80x94R3xe2x80x94xe2x80x83xe2x80x83(II) 
wherein R2 and R3 independently represent a divalent group, R4 represents a monovalent group, and R4 may bind to R2 or R3 to form a cyclic structure; the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R1 is represented by the general formula (III):
xe2x80x94R5xe2x80x94X1xe2x80x94R6xe2x80x94xe2x80x83xe2x80x83(III) 
wherein R5 and R6 independently represent a single bond or a divalent group not containing a nitrogen atom, X1 represents an oxygen atom, S(O)k wherein k represents an integer of from 0 to 2, or [(R9X2)m(R10X3)n(R11X4)p]q wherein R9, R10, and R11 independently represent a single bond or a divalent group not containing a nitrogen atom, and wherein any groups selected from R5, R6, R9, R10 and R11 may bind together to form a cyclic structure, X2, X3 and X4 independently represent an oxygen atom, S(O)r wherein r represents an integer of from 0 to 2, or a single bond, and m, n, p and q independently represent an integer of from 1 to 3;
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R1 is 2,6-pyridinediyldimethyl group (the pyridinediyldimethyl group may have one to three substituents other than a hydrogen atom on its ring);
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R2 and R3 are the same divalent groups, and R4 is a C1-4 alkyl group which may have one to three substituents other than a hydrogen atom;
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R2 and R3 are the same divalent groups, R4 is represented as COR25 wherein R25 represents a hydrogen atom, a C1-4 alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aralkyl group, or NR26R27 wherein R26 and R27 each represent a hydrogen atom, a C1-4 alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, or an aralkyl group, and said alkyl group, aryl group, heteroaryl group, heterocyclic group, and aralkyl group including those for R26 and R27 may have one to three substituents other than a hydrogen atom; and
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R1 is represented as R1Axe2x80x94R1BCOxe2x80x94R1Cxe2x80x94R1Dxe2x80x94R1Cxe2x80x94COR1Bxe2x80x94R1A wherein R1A represents a C1-4 lower alkylene group, R1B represents NH or a methylene group, R1C represents a single bond or a methylene group, R1D represent a divalent bridging cyclic hydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclic group may have one to three substituents other than a hydrogen atom.
According to further preferred embodiments of the aforementioned each invention provided are the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein Ar1 and Ar2 independently represent the aforementioned aryl group; the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein both of Ar1 and Ar2 are 4-hydroxyphenyl groups; the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R2 and R3 are the same groups, and the minimum number of bridge-forming atoms thereof is from 1 to 10, preferably 1 to 4; the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R2 and R3 are the same divalent groups optionally having a branched chain (said divalent groups may contain 1 to 3 oxygen atoms); the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein the total number of carbon atoms is 35 or less; and the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, which is used as a medicament for preventive and/or therapeutic treatment of a disease caused by over-expression of ribonucleotide reductase.
As another aspect of the present invention, provided is a ribonucleotide reductase inhibitor or a selective cancer cell proliferation inhibitor which comprises a compound represented by the aforementioned general formula (I) or (II).
As further aspects of the present invention, provided are use of the aforementioned compound or a physiologically acceptable salt thereof for the manufacture of the medicaments for treatment of cancer which comprise a compound represented by the aforementioned general formula (I) or (II), or a physiologically acceptable salt thereof as an active ingredient, preferably the medicaments for treatment of cancer in the form of a pharmaceutical composition comprising the aforementioned compound or a physiologically acceptable salt thereof together with an additive for pharmaceutical preparations; and a method for treatment of cancer which comprises the step of administering a therapeutically effective amount of a substance selected form the aforementioned compound and a physiologically acceptable salt thereof to a patient.
The present invention further provides a compound represented by the general formula (XII):
Ar23xe2x80x94Sxe2x80x94R22xe2x80x94N(R24)xe2x80x94R23xe2x80x94Sxe2x80x94Ar24 
or a salt thereof,
wherein, R22 and R23 independently represent a divalent group, R24 represents a monovalent group or a monovalent atom, and R24 may bind to R22 and/or R23 to form a cyclic structure, and may further bind to one or two C1-4 alkylene groups to form a divalent group, and Ar23 and Ar24 independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group (the aryl group may have one to three substituents other than a hydroxyl group on its ring), and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group (the heteroaryl group may have one to three substituents other than a hydroxyl group on its ring), provided that R22xe2x80x94N(R24)xe2x80x94R23 except for the part of R24 does not contain an amide bond when R22 and R23 do not form a ring, and provided that when each of Ar23 and Ar24 is a phenyl group having one hydroxyl group on the ring, not all of said phenyl groups have a tertiary alkyl group at a position on the ring adjacent to the hydroxyl group.
As a preferred embodiment of the above invention, provided is the aforementioned compound or a salt thereof, wherein two or three groups selected from the group consisting of R22, R23 and R24 form a ring or rings.
Further preferred embodiments provided are as follows:
the above compound or a salt thereof wherein R22 and R23 are the same divalent groups, and R24 is a C1-4 alkyl group which may have one to three substituents other than a hydrogen atom;
the above compound or a salt thereof wherein R22 and R23 are the same divalent groups, R24 is represented by COR125 wherein R125 represents a hydrogen atom, a C1-4 alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aralkyl group, or NR126R127 wherein R126 and R127 each represent a hydrogen atom, a C1-4 alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, or an aralkyl group, and said alkyl group, aryl group, heteroaryl group, heterocyclic group, and aralkyl group including those for R126 and R127 may have one to three substituents other than a hydrogen atom; and
the above compound or a salt thereof wherein R22xe2x80x94N(R24)xe2x80x94R23 is represented by R101Axe2x80x94R101BCOxe2x80x94R101Cxe2x80x94R101Dxe2x80x94R101Cxe2x80x94COR101Bxe2x80x94R101A wherein R101A represents a C1-4 lower alkylene group, R101B represents NH or methylene group, R101C represents a single bond or a methylene group, R101D represent a divalent bridging cyclic hydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclic group may have one to three substituents other than a hydrogen atom.
Further preferred embodiments provided are as follows:
the above compound or a salt thereof wherein Ar23 and Ar24 independently represents an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group (the aryl group may have one to three substituents other than a hydroxyl group on its ring);
the above compound or a salt thereof wherein both of Ar23 and Ar24 independently represent a hydroxy-substituted phenyl group;
the above compound or a salt thereof wherein Ar23 and Ar24 independently represent a monohydroxy-substituted phenyl group;
the above compound or a salt thereof wherein both of Ar23 and Ar24 are 4-hydroxyphenyl groups;
the above compound or a salt thereof wherein the minimum number of bridge-forming atoms of R22 and R23 are independently from 1 to 10 [The term xe2x80x9cminimum number of bridge-forming atomsxe2x80x9d used herein means a minimum number of atoms that connect one atom and the other atom to be bridged. For example, the minimum number of bridge-forming atoms is 3 for 1,3-propenylene group, 2 for 1,2-propenylene group, and 5 for 1,5-(4-butoxy-3-pentenylene) group. Also for example, the number is 3 for 1,3-phenylene group, 2 for 1,2-phenylene group, 3 for 2,4-quinolinediyl group, and 4 for 1,5-naphthylene, as well as 4 for ethylenedioxy group, 3 for malonyl group, and 4 for phthaloyl group.];
the above compound or a salt thereof wherein R22 and R23 are the same groups and each of the minimum numbers of bridge-forming atoms thereof is 1 to 10, preferably 1 to 4;
the above compound or a salt thereof wherein R22 and R23 independently represent methylene group, ethylene group, propylene group or butylene group;
the above compound or a salt thereof wherein R22 and R23 are the same groups, and represent methylene group, ethylene group, propylene group or butylene group; and
the above compound or a salt thereof wherein the total number of carbon atoms is 35 or less.
The groups that constitute the general formulas (I) and (II) will be explained specifically.
The aryl group represented by Ar1 and Ar2 in the general formula (I) may be, for example, an aryl group having 6 to 12 carbon atoms, preferably phenyl group, naphthyl group or the like. The term xe2x80x9caryl groupxe2x80x9d has the same meaning in the following description unless otherwise indicated. The heteroaryl group may be, for example, a heteroaryl group having 5 to 12 ring-constituting atoms, such as pyridyl group, pyrrolyl group, imidazolyl group, quinolinyl group, thienyl group, and furyl group. As the heteroaryl group, for example, a group comprising a 5- or 6-membered nitrogen-containing or oxygen-containing heteroaryl ring having an enol type hydroxyl group and an active methine or active methylene group, such as pyrazolone ring and pyridone ring, may preferably used. The term xe2x80x9cheteroaryl groupxe2x80x9d has the same meaning in the following description unless otherwise indicated. It is preferred that both of Ar1 and Ar2 are aryl groups, and it is more preferred that both of Ar1 and Ar2 are phenyl groups.
The number and the substituting position of the hydroxyl group or the hydroxyl group substituted with a monovalent group on the ring of the aryl group or the heteroaryl group are not particularly limited, and they preferably have one hydroxyl group. For example, when the aryl group is phenyl group, phenyl group substituted with one hydroxyl group at the p-position (4-position) may be exemplified. Examples of the monovalent group in the one to three hydroxyl groups substituted with a monovalent group present independently on the ring of the aryl group or the heteroaryl group include, but not limited thereto, linear or branched C1-6 alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group; aryl groups such as phenyl group and naphthyl group; C1-12 alkanoyl groups which may be substituted; hydroxy(C2-6)alkyl groups such as hydroxyethyl group; C7-15 aralkyl groups such as benzyl group and phenethyl group; C6-12 aroyl groups; C1-6 alkylsulfonyl groups; C6-12 arylsulfonyl groups; C1-6 alkoxycarbonyl groups; aryloxycarbonyl groups; hydroxyphenylthio(C1-6) alkyl groups; aminocarbonyl groups substituted with 0 to two C1-6 alkyl groups or C6-12 aryl groups; aminoalkylcarbonyl groups substituted with 0 to two C1-6 alkyl groups or C6-12 aryl groups; C1-6 alkoxy-substituted C1-6 alkanoyl groups, C1-6 alkylamino-substituted C1-6 alkanoyl groups, piperidinocarbonyl group, 4-piperidinopiperidinocarbonyl group, N-t-butoxycarbonyl-N-methylglycyl group and the like.
On the ring of the aforementioned aryl group or the heteroaryl group, one to three substituents other than a hydroxyl group or a hydroxyl group substituted with a monovalent group may be present. As such a substituent, examples which can be used are as follows: a halogen atom selected from fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-6 alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group; a halogenated C1-6 alkyl group such as trifluoromethyl group; a C1-6 alkoxyl group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group and tert-butoxy group; a C1-6 alkylenedioxy group such as methylenedioxy group and ethylenedioxy group; carboxyl group; a C1-6 alkoxycarbonyl group; non-substituted amino group; a C1-6 alkyl-substituted amino group such as methylamino group, dimethylamino group and ethylamino group; cyano group or the like. Among them, halogen atoms, C1-6 alkyl groups, C1-6 alkoxyl groups and the like are preferred.
In the specification, the term xe2x80x9cbridging groupxe2x80x9d means a group or an atom that can form two independent covalent bonds. In the specification, the term xe2x80x9cdivalent groupxe2x80x9d means the bridging group which can form two independent covalent bonds, and contains at least one carbon atom. The divalent group may have a chain-like or a cyclic structure, or may have a combination of portions of a chain-like structure and a cyclic structure.
R1 in the general formula (I) represents a divalent group consisting of a nonmetal bridging group, which preferably comprising atoms selected from the group consisting of carbon atom, hydrogen atom, oxygen atom, nitrogen atom, sulfur atom, and phosphorus atom, and has atoms excluding hydrogen the number of which is 1 to 80. R1 may further contain one to three halogen atoms.
These divalent groups may contain one to three unsaturated bonds, such as a double bond consisting of a carbon-carbon bond, carbon-oxygen bond, sulfur-oxygen bond, carbon-nitrogen bond, or nitrogen-nitrogen bond, or triple bond consisting of a carbon-carbon bond. Furthermore, they may contain one to three covalent bonds including any hetero atoms such as carbamoyl bond, sulfamoyl bond, ether bond, and disulfide bond as a partial structure. For example, they may contain one to three cyclic structures selected from monocyclic structures such as those consisting of benzene ring, cyclohexane ring, tetrahydrofuran ring, and pyranone ring, condensed rings such as naphthalene ring, indole ring, and quinoline ring, and bicyclo structures such as bicyclooctane ring. Furthermore, examples also include pyrrole ring, piperidine ring, indole ring, pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazine ring, indazole ring, thiazole ring and the like. When the divalent group is a cyclic group or chain-like group, or when it contains a partial chain-like structure, it may contain a branched chain.
The aforementioned ring that constitutes the divalent group, and carbon atoms and/or hetero atoms constituting the backbone of the divalent group may have one or more substituents thereon, for example, those selected from the group consisting of a halogen atom such as fluorine atom, chlorine atom, and bromine atom; a linear or branched C1-6 alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group; a linear or branched C1-6 alkoxyl group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group and tert-butoxy group (those alkyl and alkoxyl groups may have a substituent such as hydroxyl group, a C1-6 alkoxyl group, a C1-6 alkyl-substituted or non-substituted carbamoyl group, non-substituted amino group, a C1-6 alkyl-substituted amino group such as methylamino group, dimethylamino group, and ethylamino group, a C1-6 cyclic amino group such as morpholino group and piperidino group, and a C1-6 cyclic aminocarbonyl group such as morpholino group and piperidino group); a C1-6 alkylenedioxy group such as methylenedioxy group and ethylenedioxy group; carboxyl group; a C1-6 alkoxycarbonyl group; non-substituted amino group or a C1-6 alkyl-substituted amino group such as methylamino group, dimethylamino group and ethylamino group; hydroxyl group; an aryl group such as phenyl group; a C1-6 alkyl-substituted sulfonyl group; a C1-6 alkanoyl group such as acetyl group and propionyl group; a halogenated C1-6 alkanoyl group such as trifluoroacetyl group and monochloroacetyl group; an alkoxy-substituted C1-6 alkanoyl group such as methoxymethylcarbonyl group; cyano group; a C1-6 alkyl-substituted or non-substituted carbamoyl group; sulfamoyl group; carboxyl group; sulfo group; a lactone ring or a lactam ring consisting of 4 to 8 ring-constituting atoms; and a halogen atom.
Preferred examples of the divalent group represented by R1 include, for example, linear or branched C1-6 alkylene groups such as methylene group, ethylene group, propylene group, butylene group, and pentylene group; arylene groups such as p-phenylene group, m-phenylene group, 1,4-naphthylene group, and 1,5-naphthylene group; heteroarylene groups such as 2,6-pyridinediyl group; vinylene group; ethynylene group; propenylene group; propynylene group; C2-6 alkenylene groups such as 1-butenylene group, and cis- and trans-2-butenylene group, C2-6 alkynylene groups and the like. These divalent groups may have one to three substituents selected from the aforementioned substituents. Preferred examples of the alkylene group having one or more substituents include, for example, oxo(C1-6)alkylene groups such as 1-oxoethylene group, 1-oxo-2-methylethylene group, and 1-oxopropylene group; and oxy(C1-6)alkylene groups such as 1-oxypropylene group, and 2-oxypropylene group and the like. Divalent groups consisting of a suitable combination of groups selected from alkylene groups, arylene groups and heteroarylene groups are also preferred.
Those wherein R1 represents R1Axe2x80x94R1BCOxe2x80x94R1Cxe2x80x94R1Dxe2x80x94R1Cxe2x80x94COR1BR1A, wherein R1A represents a C1-4 lower alkylene group, R1B represents NH or a methylene group, R1C represents a single bond or a methylene group, R1D represents a divalent bridging cyclic hydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclic group may have one to three substituents other than a hydrogen atom, are also preferred examples of the divalent group. Examples of the divalent bridging cyclic hydrocarbon group and monocyclic hydrocarbon group include, for example, 1,1-cyclopentylene, 5,6-norbornenylene, 1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene, 1,2-cyclopentylene, 2,2-dimethyl-1,3-cyclopentylene, 1,1-cyclohexylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,3-adamantylene, 1,1-phenylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,4-naphthylene, 2,3-naphthylene, 2,6-naphthylene, 1,8-naphthylene and the like. Examples of the divalent heterocyclic group include, for example, 1,4-piperazinylene, 4-oxo-2,6-pyranylene, 2,3-pyrrolylene, 3,5-pyrazolylene, 2,3-indolylene, 2,6-pyridylene, 2,3-pyridylene, 2,4-pyridylene, 3,4-pyridylene, 2,5-pyridylene, 3,5-pyridylene, 2,3-pyrazinylene, 3,4-furylene, 4,5-imidazolylene, 1,2,3-triazol-4, 5-ylene, 7-oxabicyclo[2.2.1]heptynyl-2,3-ylene, tricyclo[4.2.1.02.5]nona-3,7-dien-3,4-ylene, 2,2-dimethyldioxolan-4,5-ylene and the like. As preferred substituents on the divalent bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclic group, those exemplified for the substituents on the rings of the aforementioned aryl group and heteroaryl group may be used.
The minimum number of bridging group-forming atoms of R1 is preferably in the range of 1 to 20, more preferably 1 to 9, and most preferably 3 to 7. The total atom number of the whole compound of the general formula (I) is preferably 50 or less.
The groups that constitute the compounds represented by the general formula (II) will be specifically explained below.
The definition of the divalent group represented by R2 and R3 is the same as that of the divalent group represented by R1 in the general formula (I), provided that particularly preferred minimum number of bridge-forming atoms of R2 and R3 is in a range of from 1 to 3.
In the formula (II), R4 represents a monovalent group or a monovalent atom. R4 may be, for example, a hydrogen atom, hydroxyl group, amidino group, amino group, an alkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, an aralkyl group which may be substituted, an alkyl group substituted with a heteroaryl group which may be substituted, or a group represented by any one of the following formulas (XIII) to (XVI):
xe2x80x94COxe2x80x94R25xe2x80x83xe2x80x83(XIII) 
wherein R25 represents a hydrogen atom, a C1-4 alkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclic group which may be substituted, or an aralkyl group which may be substituted;
xe2x80x94COxe2x80x94NR26R27xe2x80x83xe2x80x83(XIV) 
wherein R26 and R27 independently represent a hydrogen atom, a C1-4 alkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclic group which may be substituted, or an aralkyl group which may be substituted;
xe2x80x94SO2xe2x80x94R25xe2x80x83xe2x80x83(XV) 
wherein R25 has the same meaning as that defined above; and
xe2x80x94SO2xe2x80x94NR26R27xe2x80x83xe2x80x83(XVI) 
wherein R26 and R27 have the same meanings as those defined above.
Where R4 is an alkyl group which may be substituted, the alkyl group may be linear or branched, and it may contain one or more cyclic structures or one or more unsaturated bonds. The number of carbon atoms thereof may preferably be 20 or less including its substituent(s). Particularly preferred group may contain 1 to 4 carbon atoms. Preferred examples of the substituent include, but not limited thereto, halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, hydroxyl group, carboxyl group, vinyl group, ethynyl group, C3-8 cycloalkyl groups, carbamoyl group which may have a substituent on the nitrogen atom (one or two substituents selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a hydroxy-substituted C1-6 alkyl group, an aryl group, a sulfonyl group, a C1-6 alkyl-substituted sulfonyl group, a C1-6 alkanoyl group, a halogenated C1-6 alkanoyl group, a hydroxy-substituted C1-6 alkanoyl group, an alkoxy-substituted C1-6 alkanoyl group and the like), a sulfamoyl group which may have a substituent on the nitrogen atom (one or two substituents selected from those exemplified for the aforementioned carbamoyl group), C1-20 alkanoyl groups, aroyl groups, heteroarylcarbonyl groups, C1-20 alkanoylamino groups, aroylamino groups, heteroarylcarbonylamino groups, C1-20 alkylsulfonyl groups, arylsulfonyl groups, heteroarysulfonyl groups, C1-20 alkylsulfonylamino groups, arylsulfonylamino groups, heteroarylsulfonylamino groups, an ureido group which may have a substituent on the nitrogen atom (one or two substituents selected from those exemplified for the aforementioned carbamoyl group), a cyano group, an amino group which may have a substituent on the nitrogen atom (one or two substituents selected from those exemplified for the aforementioned carbamoyl group), C1-20 alkylthio groups, C1-20 alkoxyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, arylthio groups substituted with one to three hydroxyl groups, C1-20 alkoxycarbonyl groups, aryloxycarbonyl groups, heteroaryloxycarbonyl groups, a 2-hydroxyethoxy group, polyether groups (2-methoxyethoxy group, 2-(2-methoxyethoxy)ethoxy group etc.), a succinimido group, a guanidino group, aryl groups, aryl groups which are substituted with one or two hydroxyl groups, aryl groups which are substituted with 1 to 5 independently selected halogen atoms (a halogen atom has the same meaning as that defined above), heteroaryl groups, heterocyclic groups and the like.
The aryl group of the aforementioned aryl group, aroyl group, aroylamino group, arylsulfonyl group, arylsulfonylamino group, aryloxy group, and aryloxycarbonyl group, and the heteroaryl group of the aforementioned heteroaryl group, heteroarylcarbonyl group, heteroarylsulfonyl group, heteroarylsulfonylamino group, heteroaryloxy group, and heteroaryloxycarbonyl group have the same meanings as those defined above. Examples of the heterocyclic group include, for example, dioxolanyl group, morpholino group, morpholyl group, piperidyl group, dioxanyl group, imidazolyl group, thiazolyl group, pyrimidinyl group, 2,2-dimethyl-1,3-dioxolanyl group and the like.
Preferred examples of R4 include, but not limited thereto, methyl group, ethyl group, propyl group, sec-butyl group, cyclopropylmethyl group, allyl group, propargyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, carbamoylmethyl group, 2-carbamoylethyl group, 2-(N,N-dimethylcarbamoyl)ethyl group, 2-(N-morpholinocarbonyl)ethyl group, 2-(N-piperidinocarbonyl)ethyl group, sulfamoylmethyl group, acetylmethyl group, 2-(N-acetylamino)ethyl group, cyanomethyl group, 2-(N,N-diethylamino)ethyl group, 2-(N-morpholino)ethyl group, 2-(N-piperidino)ethyl group, 2-methylthioethyl group, 2-methoxyethyl group, hydroxyethoxyethyl group, methoxycarbonylmethyl group and the like.
When R4 is an aryl group which may be substituted, the number of carbon atom is preferably 20 or less including its substituent(s). Preferred examples include, for example, phenyl group which may be substituted and naphthyl group which may be substituted. When these groups have a substituent, they may have one to three substituents. Preferred examples of the substituent are those exemplified as preferred substituents for R4 when it represents the alkyl group. Among them, halogen atoms, hydroxyl group, carbamoyl group and the like are particularly preferred. When R4 is a heteroaryl group which may be substituted, the number of carbon atoms is preferably 20 or less including its substituent(s). Preferred examples include, for example, pyridyl group, thienyl group, furyl group, imidazolyl group, quinolyl group and the like. These groups may have one to three substituents selected from those exemplified as preferred substituents for R4 when it represents the alkyl group.
Where R4 is an aralkyl group which may be substituted or an alkyl group substituted with a heteroaryl group which may be substituted, the number of carbon atoms thereof is preferably 20 or less including their substituent(s). Preferred examples include, for example, benzyl group, 2-phenylethyl group, naphthylmethyl group, 2-picolyl group, 3-picolyl group, (2-furyl)methyl group, (2-thienyl)methyl group, (2-quinolyl)methyl group, 2-(2-pyridyl)ethyl group, 2-(N-imidazolyl)ethyl group and the like. These groups may have one to three substituents selected from those exemplified as preferred substituents for R4 when it represents the alkyl group. Among them, halogen atoms, hydroxyl group, carbamoyl group and the like are particularly preferred substituents.
Where R4 is a group represented by the formula (XIII) or the formula (XV), the group represented by R25 preferably has 15 or less carbon atoms, and it may have one to three substituents selected from those exemplified as preferred substituents for R4 when it represents the alkyl group. The aryl group, heteroaryl group, heterocyclic group and aralkyl group for R25 have the same meanings as those defined above. Preferred examples of R4 include, for example, acetyl group, propionyl group, benzoyl group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group, benzylcarbonyl group, methanesulfonyl group, benzenesulfonyl group and the like.
Where R4 is a group represented by the formula (XIV) or the formula (XVI), those groups represented by R26 and R27 preferably have 15 or less carbon atoms, and they may have one to three substituents selected from those exemplified as preferred substituents for R4 when it represents the alkyl group. In addition, R26 and R27 may bind to each other to form a ring structure. Preferred examples of R4 include, for example, aminocarbonyl group, N-methylaminocarbonyl group, N-phenylaminocarbonyl group, N-(2-pyridylamino)carbonyl group, N,N-dimethylaminocarbonyl group, N,N-diethylaminocarbonyl group, N-morpholinocarbonyl group, N-piperidinocarbonyl group, aminosulfonyl group, N,N-dimethylaminosulfonyl group, N,N-diethylaminosulfonyl group, N-morpholinosulfonyl group, N-piperidinosulfonyl group and the like.
The ring structure which is formed by R4 together with R2 or R3 includes saturated and unsaturated ring structures. Examples of the ring include, for example, saturated or unsaturated 3- to 18-membered monocyclic rings or condensed rings, such as pyrrole ring, piperidine ring, indole ring, pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazine ring, indazole ring, and thiazole ring. These rings may be partially or fully reduced or oxidized. Furthermore, they may further bind to one or two C1-4 alkylene groups to form a divalent group.
A compound in which one monovalent group such as an alkyl group further bind to a nitrogen atom in the general formula (II) to form a quaternary salt of the nitrogen atom may also be used as an active ingredient of the medicament for treatment of cancer of the present invention. As a counter ion of the quaternary salt, for example, iodine ion, bromine ion, chlorine ion, perchlorate ion, sulfate ion, phosphate ion, sulfamate ion, acetate ion, lactate ion, citrate ion, tartrate ion, malonate ion, methanesulfonate ion, ethanesulfonate ion, hydroxyethanesulfonate ion, benzenesulfonate ion, p-toluenesulfonate ion, and cyclohexylsulfamate ion may be used. Iodine ion, bromine ion, chlorine ion, and perchlorate ion can be preferably used. As the monovalent group, C1-6 alkyl groups such as methyl group are preferred.
Divalent groups preferred as R1, R2, and R3 in the general formula (I) and (II) will be exemplified blow. However, the divalent group which can be used for the compound as the active ingredient of the medicament for treatment of cancer of the present invention is not limited to these examples (in the structures, Me represents methyl group). 
The bisaryl compounds represented by the aforementioned general formula (I) have inhibitory activity against ribonucleotide reductase, and can selectively inhibit cancer cell proliferation. Therefore, they can be used as an active ingredient of a medicament for treatment of cancer, which can be administered to mammals including human. Types of cancers to be treated by the medicament of the present invention are not particularly limited, and the medicament can be applied to solid cancers such as stomach cancer, lung cancer, colon cancer, liver cancer, kidney cancer, breast cancer, uterus cancer, skin cancer and brain tumor, as well as non-solid cancers such as leukemia and lymphoma.
In addition, they are also useful as an active ingredient of medicaments for preventive and/or therapeutic treatment of various diseases in mammals including human accompanied by unusual expression of ribonucleotide reductases deriving from host mammals themselves, viruses, bacteria and the like, for example, herpes syndrome caused by unusual proliferation of herpes simplex virus, acquired immune deficiency syndrome caused by unusual proliferation of AIDS virus and the like. Furthermore, the aforementioned compounds, per se, can also be used as ribonucleotide reductase inhibitors such as reagents in the fields of biochemistry, pharmacology, genetic engineering and the like. As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of the compounds of the aforementioned general formula (I) and salts thereof, and hydrates thereof and solvates thereof can be used, as well as any combinations of two or more of substances selected from said group.
Although the aforementioned substances, per se, may be used as the medicament of the present invention, it is generally preferred that the medicament is provided for administration as a pharmaceutical composition that can be prepared by using one or more pharmaceutically acceptable additives. Administration route of the medicament of the present invention is not particularly limited, and oral or parenteral administration may be selected. Examples of the pharmaceutical compositions suitable for parenteral administration include, for example, injections suitable for intravenous, intraarterial, intraperitoneal or intrapleural injection, drip infusions, preparations for intrarectal administration (suppositories) and the like. Examples of the pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, granules, powders, syrups and the like. However, applicable pharmaceutical compositions are not limited to these examples, and those skilled in the art can select a suitable form of composition from available pharmaceutical compositions.
For example, for the manufacture of injections, the aforementioned substances as an active ingredient may be dissolved in a diluent available to those skilled in the art (for example, physiological saline, glucose solution for injection, lactose solution for injection, mannitol solution for injection and the like), and then the solution may be subjected to an appropriate sterilization treatment such as filtration sterilization, and filled in hermetic containers such as ampoules. Preparation for injection in a lyophilized form or powder for injection mixed with sodium chloride may also be prepared according to the Japanese Pharmacopoeia. As the pharmaceutical additives, for example, carriers such as auxiliaries such as polyethylene glycol and HCO-60 (surfactant; Nikko Chemical Co. Ltd.), ethanol and/or liposome and cyclodextrin may be incorporated. Pharmaceutical compositions suitable for oral administration or intrarectal administration can be prepared by mixing the aforementioned substances with appropriate pharmaceutical additives such as excipients, disintegrating agents, binders, lubricants, suspending agents, isotonic agents, and emulsifiers in a conventional manner, and formulating the mixture into an appropriate form.
Dosage and administration frequency of the medicament of the present invention are not particularly limited. When the medicament of the present invention is used for treatment of cancer, it can be administered, for example, via intravenous route in an amount of 0.01 to 100 mg/kg (based on the weight of the active ingredient) at intervals of every week to every 3 weeks. It is desirable to suitably adjust the dosage and administration frequency depending on various conditions, for example, route of administration, a kind of an active ingredient, i.e., the compound of the aforementioned formulas (I) to (III), the age and body weight of patients, the condition, and frequency and severity of side effects such as bone marrow suppression.
The bisaryl compounds represented by the aforementioned general formula (I) may have one to three asymmetric carbons depending on the kind of the substituents. Furthermore, a sulfur atom may also serve as an asymmetric center. Any optical isomers in an optically pure form based on one to three asymmetric carbons, any mixtures of the aforementioned optical isomers, and racemates, as well as diastereomers based on two or more asymmetric carbons, any mixtures of such diastereomers and the like may be used as the active ingredient of the medicament of the present invention. As the active ingredient of the medicament of the present invention, those in free form encompassed by the aforementioned formula as well as physiologically acceptable salts thereof may be used.
Examples of such salts include, for example, hydrochlorides, sulfates, phosphates, sulfamates, acetates, lactates, citrates, tartrates, malonates, methanesulfonates, ethanesulfonates, hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and the like. These salts can be prepared by dissolving the aforementioned compound as free base in water, an aqueous organic solvent such as alcoholic solvent or a suitable organic solvent containing a corresponding acid to form a uniform solution, and isolating a salt after evaporation of water or the organic solvent, or allowing the compound in free form to react with an acid in an organic solvent. In the latter case, for example, the resulting salt can be directly isolated, or recovered by evaporation of the solvent. As the active ingredient of the medicament of the present invention, the aforementioned compounds in free form and salts thereof, and in addition, hydrates thereof and solvates thereof can be used. Examples of the organic solvent for forming the solvates include, for example, physiologically acceptable solvents such as ethanol and ethylene glycol.
Specific examples of the compounds most suitably used for the medicament of the present invention will be listed below. However, the active ingredient of the medicament of the present invention is not limited to the following compounds (in the tables, the serial numbers in the first left column indicate the compound numbers, Ph represents phenyl group, and p-HO-Ph represents p-hydroxyphenyl group. In Table 3, xe2x80x9cBxe2x80x9d represents p-hydroxyphenylthio group, Me represents methyl group, Et represents ethyl group, and Ac represents acetyl group).
According to the present invention, there are provided novel compounds represented by the general formula (XII):
Ar23xe2x80x94Sxe2x80x94R22xe2x80x94N(R24)xe2x80x94R23xe2x80x94Sxe2x80x94Ar24. 
Ar23 and Ar24 in the general formula (XII) have the same meanings as the aforementioned Ar1 and Ar2. However, those wherein each of Ar23 and Ar24 is a phenyl group having one hydroxyl group on the ring, and both of these phenyl groups have a tertiary alkyl group at a position on the ring adjacent to the hydroxyl group are excluded from the scope of the invention concerning the novel compounds of the present invention. R22, R23 and R24 in the general formula (XII) have the same meanings as the aforementioned R2, R3, and R4, provided that, when R22 and R23 do not form a ring. R22xe2x80x94N(R24)xe2x80x94R23 except for the part of R24 does not contain an amide bond. Furthermore, in the above definitions, R125, R126, R127, R101A, R101B, R101C, and R101D have the same meanings as R25, R26, R27, R1A, R1B, R1C and R1D, respectively.
Examples of the divalent group suitable as R22, R23, or R22xe2x80x94N(R24)xe2x80x94R23 will be exemplified below. However, the divalent group which can be used for the compound of the present invention is not limited to these examples. 
Particularly preferred compounds of the present invention represented by the formula (XII) will be specifically exemplified below. However, the compounds of the present invention are not limited to the following exemplary compounds.
The compounds of the present invention may form an acid addition salt, and may also form a base addition salt depending on the types of substituents. Examples of the acid addition salt include, but not limited thereto, mineral acid salts such as hydrochlorides, sulfates and nitrates, and organic acid salts such as p-toluenesulfonates, methanesulfonates, acetates, chloroacetates, oxalates, trifluoromethanesulfonates, and quinolinesulfonates. When they form a base addition salt, metal salts such as sodium salts and potassium salts, ammonium salts such as ammonium salts and triethylammonium salts and the like may be used. The compounds of the present invention may also form intramolecular zwitter ions based on a phenolic hydroxyl group and a basic group, which also fall within the scope of the present invention. Furthermore, the compounds of the aforementioned formula (XI) and formula (XII) in free form or any salts thereof, and any hydrates or any solvates of the compounds in free form or salts thereof fall within the scope of the present invention. Solvents that can form solvates are not particularly limited. For example, the solvate may be formed with methanol, ethanol, acetone, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide or the like.
The compounds of the present invention may have one or more asymmetric carbons depending on the types of the substituents. Furthermore, a sulfur atom may also serve as an asymmetric center. Any optical isomers in optically pure form based on one or more asymmetric carbons, mixtures of the optical isomers, racemates, diastereomers based on two or more asymmetric carbons, mixtures of the diastereomers and the like all fall within the scope of the present invention.
Two or three groups selected from R22, R23, and R24 may bind to each other, via a divalent group if required, to form a saturated or unsaturated cyclic structure. In that case, the nitrogen atom to which R24 binds may be an atom that constitutes the ring. Examples of the ring include, for example, pyrrole ring, piperidine ring, indole ring, pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazine ring, indazole ring, thiazole ring and the like. These rings may have a partially or completely reduced ring structure. Furthermore, those wherein one more monovalent group such as an alkyl group further binds to the nitrogen atom to which R24 binds to form a quaternary salt also fall within the scope of the present invention. The counter ion of the quaternary salt may be, for example, iodide ion, bromide ion, chloride ion, perchlorate ion and the like. As the monovalent group, C1-6 alkyl groups such as methyl group and the like are preferred.
The methods for preparing the bisaryl compounds represented by the aforementioned general formulas (I), (II) and (XII) are not particularly limited, and they can be synthesized via various synthetic routes. Methods for preparing typical compounds of the present invention are specifically disclosed in Examples set out below, and accordingly, those skilled in the art will readily prepare bisaryl compounds falling within the scopes of the aforementioned general formulas by referring to the method described in Examples, adding suitable alterations and modifications to the methods, if required, and suitably choosing starting materials and reagents. For the preparation, one step, or several combined steps selected from various condensation, addition, oxidation, and reduction reactions and the like can be used. These reactions are detailed in literature. For example, various methods mentioned as unit operations and starting materials disclosed in xe2x80x9cJikken Kagaku Kozaxe2x80x9d (Maruzen Co., Ltd., each separate volume of the first to the 4th edition are available) can be preferably used.
For example, it may be preferable to use a mercapto compound, an amine compound and the like for a starting material from viewpoints of a reaction operation and an yield. For example, unit operations such as synthesis of thioether (sulfide) and synthesis of ester; reactions of mercapto group with reactive functional groups such as vinyl group, halogen atoms (including haloalkyl groups), epoxy group, aziridine ring, acyl halide groups, and isocyanate group; and amination reaction, amidation reaction, alkylation reaction and the like are well known to those skilled in the art. Therefore, it is possible to chose suitable methods from the conventional methods considering an yield, easiness of reaction and the like.
For example, in these production methods, when any of the defined groups are changed under the condition of the reaction steps, or unsuitable to proceed the reaction steps, desired steps may be efficiently performed by using techniques commonly used in the synthetic organic chemistry, for example, protection and deprotection of functional groups, or treatments including oxidation, reduction, and hydrolysis. Isolation and purification of synthetic intermediates and target compounds in the aforementioned steps can be performed by common techniques in the field of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography methods and the like. In addition, synthetic intermediates may be used in subsequent steps without isolation.